It has for a long time been known that human milk in several ways is anti-inflammatory due to the fact that it is poor in initiators and mediators of inflammation but rich in anti-inflammatory agents (see e.g. Goldman A. S., et al., Anti-inflammatory properties of human milk, Acta Paediatr. Scand. 75:689-695, 1986). Human milk also contains several soluble anti-infective components, such as lactoferrin (see e.g. Hanson L. {dot over (A)}., et al., Protective factors in milk and the development of the immune system, Pediatrics 75:172-176, 1983).
Lactoferrin is a single chain metalbinding glycoprotein with a molecular weight of 77 kd. It has been found that the structural domain of lactoferrin responsible for the bactericidal properties is a pepsin-cleaved fragment called lactoferricin (see e.g. Bellamy W., et al., Identification of the bactericidal domain of lactoferrin, Biochim. Biophys. Acta 1121:130-136, 1992, and Bellamy W., et al., Antibacterial spectrum of lactoferricin B, a potent bactericidal peptide derived from the N-terminal region of bovine lactoferrin, J. Appl. Bact. 73:472-479, 1992).
Lactoferrin receptors are found on many types of cells including monocytes and macrophages, lectinstimulated human peripheral blood lymphocytes, brushborder cells, and tumour cell lines.
Several patent publications describe the possible use of lactoferrin for treatment of infections or inflammations. In WO 98/06425, e.g., it is disclosed that lactoferrin and lactoferricin can be used for treatment and prevention of infections, inflammations and tumours.
EP-A-0 629 347 describes an antimicrobial agent containing (A) lactoferrin hydrolysate and/or one or more of antimicrobial peptides derived from lactoferrins, and (B) one or more compounds selected from the group consisting of metal-chelating protein, tocopherol, cyclodextrin, glycerine-fatty acid ester, alcohol, EDTA or a salt thereof, ascorbic acid or a salt thereof, citric acid or a salt thereof, polyphosphoric acid or a salt thereof, chitosan, cysteine, and cholic acid as the effective components thereof. This antimicrobial agent is intended for treatment of products, and especially for safely treating e.g. food and medicines. The agent according to this publication is thus a new preservative. In the publication several peptide sequences are given and some of them resemble the peptides according to the invention, although there are several important differences described further below.
Even though native human lactoferrin and lactoferricin have been shown to have desired anti-inflammatory, anti-infectious and anti-tumoural properties they cannot be used clinically on a broad basis since they are very expensive substances due to high production costs.